Field of the Invention
The present invention relates to a method for enzymatically preparing a peptide for improving brain function, especially a peptide for improving or preventing amnesia. Specifically, it relates to a method which involves hydrolyzing milk casein with an enzymatic catalyst comprising a protease to prepare a hydrolysate rich in a peptide having the above action.
The present invention also relates to a food or drink or a pharmaceutical composition comprising the above hydrolysate.
Background Art
Symptoms and diseases caused by decreased brain function include depression, schizophrenia, deliria, and dementias (such as cerebrovascular dementia and Alzheimer disease). Particularly, an increase in dementia patients has become a major social problem with the aging of modern society. The symptoms of dementia depend on individuals. Examples of symptoms observed in common include memory disorder, disorientation, and decreased ability to judge/think. Among dementias, those from which many patients suffer are cerebrovascular dementia and Alzheimer disease. For example, for cerebrovascular dementia, cognition/memory disorder appears because decreased cerebral blood flow damages neuronal cells in the cerebral cortex and the hippocampus. Thus, a drug improving cerebral blood flow and a drug protecting cerebral neurons are applied in addition to treating underlying diseases including hypertension, diabetes, and hypercholesterolemia which potentially cause cerebrovascular disorder. For Alzheimer disease, whose cause remains to be clearly elucidated, the decreased function of cholinergic nerve is considered to be one of the causes thereof because a decrease in the level of acetylcholine as an intracerebral neurotransmitter is observed in patients with the disease (for example, Bartus, R. T. et al., Science, 217: 408-414 (1982)). Therefore, for Alzheimer disease, a therapeutic method is predominant which is intended to prevent the decrease of function of cholinergic nerve by increasing the level of acetylcholine.
Currently, as therapeutic drugs for Alzheimer disease are commercially available, for example, acetylcholinesterase inhibitors such as donepezil hydrochloride. However, acetylcholinesterase inhibitors such as donepezil hydrochloride have a disadvantage that they cannot be administered for a long period of time because of their liver toxicity and strong side effects and are also expensive.
As a report on a peptide having the effect of improving amnesia, it is reported, for example, that lateral ventricular injection or oral administration of 300 mg/kg of XPLPR (where X is L, I, M, F, or W) has the effect of improving scopolamine-induced amnesia, suggesting the release of acetylcholine through brain C3a receptor as one of mechanisms therefor (JP Patent No. 3898389). Scopolamine is considered to cause a decrease of the function of cholinergic nerve as a muscarinic receptor antagonist, and act as an agent inducing brain dysfunction; for an improving action in a model animal for the development of therapeutic drugs for Alzheimer disease, the effect of improving and/or enhancing brain function can be demonstrated, for example, by a behavioral test such as a Y-shaped maze test, an eight-arm maze test, or a passive avoidance test. However, each of the peptides is required to be orally administered at a large dose or intraperitoneally administered, intraventricularly injected, or by other delivery route to exhibit the action, and does not have a sufficient effect as an orally ingestable substance. There is also no report in which the peptide and analogs thereof according to the present invention have been evaluated, and the action thereof involved in improving brain function has been unknown.
Thus, with the progress of the aging of the society, there is a strong need for the development of such a pharmaceutical product as to have the effect of preventing and also improving symptoms or diseases caused by decreased brain function and further a safer compound excellent in application to food.
Meanwhile, it is reported that the hydrolysate obtained by hydrolyzing casein with an enzyme has pharmacological actions such as a blood-pressure-lowering action, a smooth muscle-contracting action, and an anemia-improving action, and can be used in a nutrient preparation and a mother's milk substitute, and the like (International Publication WO 96/13174, JP Patent Publication (Kokai) No. 06-128287 (1994), JP Patent Nos. 1893866 and 1572761, U.S. Patent No. 6,994,987, JP Patent Publication (Kokoku) No. 07-032676 B (1995), and JP Patent No. 1907911); however, no report on the brain function-improving action thereof is found.